In 1967, scientists used a simple climate model to predict that human-caused increases in atmospheric CO2 should warm Earth’s troposphere and cool the stratosphere. This important signature of anthropogenic climate change has been documented in weather balloon and satellite temperature measurements extending from near-surface to the lower stratosphere. Stratospheric cooling has also been confirmed in the mid to upper stratosphere, a layer extending from roughly 25 to 50 km above the Earth’s surface (S25 − 50). To date, however, S25 − 50 temperatures have not been used in pattern-based attribution studies of anthropogenic climate change. Here, we perform such a “fingerprint” study with satellite-derived patterns of temperature change that extend from the lower troposphere to the upper stratosphere. Including S25 − 50 information increases signal-to-noise ratios by a factor of five, markedly enhancing fingerprint detectability. Key features of this global-scale human fingerprint include stratospheric cooling and tropospheric warming at all latitudes, with stratospheric cooling amplifying with height. In contrast, the dominant modes of internal variability in S 25 − 50 have smaller-scale temperature changes and lack uniform sign. These pronounced spatial differences between S25 − 50 signal and noise patterns are accompanied by large cooling of S25 − 50 (1 to 2 ° C over 1986 to 2022) and low S25 − 50 noise levels. Our results explain why extending “vertical fingerprinting” to the mid to upper stratosphere yields incontrovertible evidence of human effects on the thermal structure of Earth’s atmosphere.